Project Summary/Abstract Most injuries to the spinal cord lead to a disruption of ascending and descending fiber tracts followed by loss of sensation and voluntary movement below the level of the lesion. These neurological deficits are often irreversible, in part due to the presence of inhibitory proteins that prevent axonal regeneration. With more limited spinal cord injuries there may be some degree of spontaneous behavioral enhancement. This improvement is thought to be the result of subtle structural reorganization or plasticity of spared neighboring neurons, partially compensating for neurons damaged by the injury. While it has been known for some time that increased nervous system plasticity (e.g. caused by trophic factors in animal models, exercise or physiotherapy in human patients) leads to functional improvements, the underlying molecular and cellular regulatory mechanisms in the adult remain largely unknown. Of particular interest, our recent studies show that at the molecular level there is a strong connection between the suppression of synaptic plasticity and inhibition of axonal regeneration. This proposal examines these possible links with respect to two major classes of axon growth inhibitors: myelin-associated proteins, and proteoglycans in the extracellular matrix. In one major aim, it is proposed to test whether myelin-associated inhibitors of regeneration suppress activity-dependent synaptic plasticity in the adult mammalian CNS. We will employ a combination of electrophysiological studies, mouse genetics, and in vitro cell culture experiments: (i) to assess the role of myelin inhibitors at the CNS synapse, (ii) to define their mechanism(s) of action and (iii) to elucidate their role in neuronal activity and neuronal structure. The emphasis is on both the myelin inhibitory proteins and their receptors NgR1 and PirB. In a second major aim, we have recently identified an interaction between these receptors and CNS proteoglycans, and now propose to investigate the functional significance of this link with respect to axonal growth. In particular, does the myelin protein receptor NgR1 act in a proteoglycan-dependent manner? The objective of this work is to define mechanisms that limit neural plasticity and axon regeneration in the adult mammalian central nervous system as these mechanisms are potential targets for therapeutic augmentation.